Organ preservation apparatus and methods

ABSTRACT

This invention is a transportable organ preservation system that substantially increases the time during which the organ can be maintained viable for successful implantation into a human recipient. A chilled oxygenated nutrient solution is pumped through the vascular bed of the organ after excision of the organ from the donor and during transport. The device of the present invention uses flexible permeable tubing to oxygenate the perfusion fluid while the CO.sub.2 produced by the organ diffuses out of the perfusion fluid. One pressurized two liter “C” cylinder that contains 255 liters of oxygen at standard temperature and pressure can supply oxygen for up to 34 hours of perfusion time. The device uses a simple electric pump driven by a storage battery to circulate the perfusion fluid through the organ being transported. The vessel containing the organ to be transported is held at 4.degree. C. by coolant blocks.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/692,394 filed Oct. 23, 2003, now U.S. Pat. No. 7,176,015, which is acontinuation of Ser. No. 09/953,338, filed Sep. 14, 2001, now U.S. Pat.No. 6,677,150. The parent application is hereby incorporated herein byreference in its entirety to provide continuity of disclosure.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

FIELD OF THE INVENTION

This invention relates to a transportable organ preservation system andmore particularly to a preservation system, which substantiallyincreases the time enroute during which the organ can be maintainedviable for successful implantation into a human recipient. A chilledoxygenated nutrient solution is pumped through the vascular bed of theorgan after excision of the organ from the donor and during transport.

BACKGROUND OF THE INVENTION

The surgical transplantation of organs has been successfully performedsince 1960 owing to the improvement of surgical techniques, theintroduction of by-pass circulation and the development of drugs thatsuppress immune rejection of the donor organ. At the present time, thedonor organ is harvested under sterile conditions, cooled to about4.degree. C. and placed in a plastic bag submerged in a buffered saltsolution containing nutrients, and finally transplanted into therecipient. The solution is not oxygenated and is not perfused throughthe organ blood vessels.

The lack of donor organ availability, particularly hearts, lungs, andlivers, is a limiting factor for the number of organ transplants thatcan be performed. At the present time, less than 25% of patients whorequire a heart transplant receive a new heart, and less than 10% ofpatients who require a lung transplant receive one. A majorconsideration is the length of time that a donor organ will remainviable after it is harvested until the transplant surgery is completed.For hearts, this interval is about four hours. The donor heart must beharvested, transported to the recipient, and the transplant surgerycompleted within this time limit. Thus, donor hearts can be used only ifthey are harvested at a site close to the location where the transplantsurgery will take place.

It has long been known that organs will survive ex vivo for a longertime if they are cooled to 4.degree. C. and actively perfused throughtheir vascular beds with a buffered salt solution containing nutrients,and that ex vivo survival of an isolated organ can be further extendedif the solution is oxygenated. Several factors play a role in theprolonged survival. At 4.degree. C. the metabolism is greatly reduced,lowering the requirements for nutrients and oxygen, and the productionof lactic acid and other toxic end products of metabolism are alsogreatly reduced. Circulation of the perfusion fluid replenishes theoxygen and nutrients available to the tissue, and removes the lacticacid and other toxic metabolites. The buffered solution maintains the pHand tonic strength of the tissue close to physiological.

Perfusion that allows the transport of a harvested organ from a siteremoved from the location where the transplant surgery will be carriedout requires the use of a light weight portable device that operatesunder sterile conditions for pumping the cold buffered nutrient saltsolution through the organ blood vessels, and in which the organ alsocan be transported from the site of harvesting to the site oftransplantation. In order for one person to carry the entire assemblywithout assistance, and to transport it in an auto or airplane, itshould be compact, sturdy and lightweight. The system for loading theperfusion fluid should be simple and allow minimal spillage. There mustbe a means for oxygenating the perfusion fluid. The device requires apump with a variably adjustable pumping rate, which pumps at a steadyrate once adjusted. Sterility must be maintained. To be completelyportable, the device should contain a source of oxygen, an energy sourceto operate the pump, and should be housed in an insulated watertightcontainer that can be loaded with ice. An entirely satisfactory deviceis not currently available.

The use of a lightweight, cooled, self-contained perfusion device wouldhave a number of beneficial consequences. (1) The organs would be inbetter physiological condition at the time of transplantation. (2)Prolonging the survival time of donor organs will enlarge the pool ofavailable organs by allowing organs to be harvested at a distance fromthe site of the transplant surgery in spite of a longer transport time.(3) It would allow more time for testing to rule out infection of thedonor, for example with AIDS, hepatitis-C, herpes, or other viral orbacterial diseases. (4) The pressure on transplant surgeons to completethe transplant procedure within a short time frame would be eased.Transplant surgeons are often faced with unexpected surgicalcomplications that prolong the time of surgery. (5) Better preservationof the integrity of the heart and the endothelium of the coronaryarteries at the time of transplantation may also lessen the incidenceand severity of post-transplantation coronary artery disease.

On Oct. 12, 1999 the assignee of the present invention was granted U.S.Pat. No. 5,965,433 for a portable organ profusion/oxygenation modulethat employed mechanically linked dual pumps and mechanically actuatedflow control for pulsatile cycling of oxygenated perfusate.

The aforementioned patent contains an excellent description of the stateof the art in the mid-nineties and the problems associated withtransport systems for human organs. The patent also outlines the manyadvantages obtained by the ability to extend the transport time fromapproximately 4 to 24 hours.

Human organ transplantation is plagued by limitations due toinsufficient time to transport an organ while maintaining its viabilityand by an inadequate donor pool. The present invention willsignificantly diminish the problem of limited transport time byproviding an apparatus that will extend the transport time to up to 48hours. This increased time will inherently increase the size of thedonor pool and will allow for extensive disease testing and matching.

The present invention will also greatly reduce damage to the organ beingtransported and will allow organs from post-mortem donors to be used.Today, organs are only harvested from donors who are brain-dead butwhose organs have never ceased to function.

Currently, an organ is transported by putting the organ in a plastic bagof storage fluid, put on ice inside a cooler. In 4 hours, 12% of thetransported organs “die” or become unusable, and all the organs aredegraded.

A particular advantage of the transport system of the present inventionis that it is easily loaded and unloaded by double-gloved surgicalpersonnel and that the fittings require minimal dexterity to assembleand disassemble.

Another advantage of the present invention is that it does not use theflexible permeable membranes of the prior art that, due to theirconstant flexing, are subject to fatigue stresses and rupture withcatastrophic results.

DESCRIPTION OF THE PRIOR ART

For the thirty-year history of organ transplantation surgery,maintaining the quality and viability of the organ has been an enormouschallenge. The current method of transport, called topical hypothermia(chilling the organ in a cooler), leaves 12% of organs unusable becauseof their deteriorated physiological condition. Thousands of people dieeach year while on an ever-expanding waiting list. The need is great fora truly portable device that nurtures and oxygenates the organthroughout the entire ex-vivo transport.

Currently, when hearts, lungs, liver and certain other organs areharvested from a donor, medical teams have about 4 hours to transplantthe harvested organ into the recipient. Damage to the organ at thecellular level occurs even during this short period.

Hypothermic, oxygenated perfusion devices are known in the art and haveproven successful in maintaining viability of a human heart for 24 hoursex vivo in laboratory settings. While different devices are availablefor laboratory use under constant supervision, none are trulyindependently functioning and portable. For example, Gardetto et al.,U.S. Pat. No. 5,965,433 describes an oxygen driven dual pump system witha claimed operating capacity of 24 hours using a single a 250 literoxygen bottle. The intent of this device was to provide a user-friendlydevice that would be “hands off” after the organ was placed in the unit.Four major problems were evident. (1) The unit contains no bubble trapand removing bubbles is difficult and time consuming. (2) The lubricantin the pumps dries out after 10 or fewer hours of operation and thepumps stop. (3) At lower atmospheric pressure such as in an aircraft inflight, the pump cycles rapidly due to the reduced resistance topumping, risking the development of edema in the perfused organ; and (4)Two bottles of oxygen failed to produce more than 16 hours of steadyoperation.

Doerig U.S. Pat. No. 3,914,954 describes an electrically drivenapparatus in which the perfusate is exposed to the atmosphere, breakingthe sterility barrier. It must be operated upright, consumes oxygen athigh rates, and is heavy. The requirement for electric power and thenecessity for a portable source of electric power severely limit theportability of this unit.

O'Dell et al., U.S. Pat. No. 5,362,622, U.S. Pat. No. 5,385,821, andO'Dell U.S. Pat. No. 5,356,771 describes an organ perfusion system usinga fluidic logic device or a gas pressure driven ventilator to cyclicallydeliver gas to a sealed chamber connected to the top of the organcanister. Cyclical delivery of gas under pressure to the upper sealedchamber serves to displace a semi-permeable membrane mounted between thegas chamber and the organ canister. Cyclical membrane displacement actsto transduce the gas pressure into fluid displacement on the oppositeside, providing flow of the perfusing solution.

The membrane is chosen for its permeability to gas but not to water.This permits oxygen to flow through the membrane to oxygenate the fluidand vent carbon dioxide from the fluid. The intent of such devices is toprovide a system that uses no electricity, uses low gas pressure toachieve perfusate flow, has few moving parts, provides oxygenation ofthe fluid, can be operated in a non-upright position, isolates the organand perfusate from the atmosphere, is of compact size and low weight tobe portable.

While these systems may work in experimental settings, they fail to meetcriteria claimed by the developers. For example, the amount of oxygennecessary to cycle the membrane is very large. When calculated over a24-hour period, it would require 4 large tanks of oxygen to assurecontinuous operation. This amount of oxygen fails to meet the definitionof portable. The pressure and volume of oxygen required to cycle themembrane is sufficient to cause tearing of the membrane or displacing itfrom its margins. Either of these occurrences would be catastrophic tothe organ. The manner in which fluid is cycled into the organ chamberattempts to perfuse both within and around the organ, providing freshlyoxygenated fluid to infiltrate and surround the organ. This procedure iswithout physiological basis since normally, oxygenation is achieved byoxygen diffusion outward from the organ's vascular bed.

All of these devices use a permeable membrane permeable to gas but notto water so that oxygen or other gas mixtures can be driven through themembrane into the perfusate and can vent CO.sub.2, produced by theorgan, from the perfusate.

The successful use of permeable membranes that are subjected torepetitive variations in pressure over long periods of time depends uponthe membrane having elastomeric properties to withstand such repeatedflexing without tearing or rupturing. Gas permeable membranes are notbuilt to possess such elastomeric properties.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a method and apparatus which allows onepressurized two liter “C” cylinder that contains 255 liters of oxygen atstandard temperature and pressure to supply up to 34 hours of perfusiontime and uses a simple electric pump driven by a storage battery tocirculate the perfusion fluid through the organ being transported.

The device of the present invention is devoid of flexible membranes andinstead uses flexible permeable tubing to oxygenate the perfusion fluidwhile the CO.sub.2 produced by the organ diffuses out of the perfusionfluid.

The vessel containing the organ to be transported is held at 4.degree.C. (39.degree. F.) by coolant blocks.

All components are designed to use injection molding as themanufacturing method.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

The advantages and features of the invention described herein can beunderstood in more detail by reference to the following description anddrawings appended hereto and which form part of this specification.

The appended drawings illustrate a preferred embodiment of the inventionand are therefore not to be considered limiting of its scope.

FIG. 1 is a hydraulic circuit diagram showing the interconnection of theprincipal components of a portable perfusion apparatus of the presentinvention;

FIG. 2 is an expanded perspective view of the apparatus of the presentinvention;

FIG. 3 is a plan view of the apparatus of the present invention;

FIG. 4 is a cross-section view of the apparatus of the present inventiontaken along the lines 1A-1A of FIG. 3;

FIG. 5 is a cross-section view of the apparatus of the present inventiontaken along the lines 1B-1B of FIG. 3;

FIG. 5 a is a detailed view of the lid-container sealing arrangement;

FIG. 5 b is a perspective view of the adapter;

FIG. 6 is a sideview of the apparatus of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

As shown in FIG. 1, one embodiment of the perfusion apparatus of thepresent invention includes a compressed oxygen canister 17, anoxygenator chamber assembly 21, an organ container 8, an organ containerlid 9, a bubble chamber 11, a pump assembly 4 and one or more coolingblocks or freezer packs 6.

The oxygen supply 17 is coupled to the oxygenator 21 through a pressureregulator 18. The oxygenator 21 is attached to the side of the reservoiror organ container 8. Similarly, the bubble chamber 11 is attached tothe organ container 8 thus providing a compact assembly. The functionand operation of the oxygenator 21 and the bubble chamber 11 will bedescribed in more detail hereinafter.

As shown in FIG. 3, the organ container 8 together with the oxygenatorassembly 21 and the bubble chamber 11 occupy approximately one third ofa cooler 2 while the oxygen canister 17 together with the pump assembly4 and cooling blocks 6 occupy the remainder of the cooler 2. Theaforementioned components are mounted on a tray 3 as shown in FIG. 3.The cooler provides for a compact and readily transportable assembly ofapproximately 50 quarts. The weight of the entire assembly, includingthe organ to be transported and the perfusion fluid does not exceed 50pounds.

FIG. 2 shows how the main components, in the oxygen canister 17, theoxygenator assembly 21, the organ container 8, the bubble chamber 11,the pump assembly 4 and cooling blocks 6 fit onto tray 3 and into thecontainer 2.

The components are designed to be manufactured by injection moldingusing a polycarbonate resin such as Makralon.RTM. Rx-1805. Thisthermoplastic resin is a transparent polycarbonate formulated to provideincreased resistance to chemical attack from intravenous (IV) fluidssuch as lipid emulsions.

The cover 9 for the organ container is sealed to the container 8 bymeans of a standard o-ring 10 as shown in FIG. 5 a. Suitable fastenersare used to hold the cover 9 in place.

The cover 11 a for the bubble chamber 11 and the cover 14 for theoxygenator 21 are glued in place using a U.V. cure adhesive.

The organ and perfusion fluid are thus sealed from the atmosphere andsterile conditions are maintained.

The tubing 19 used to connect the various components together is madefrom USC class 6, manufactured by many suppliers. Quickconnect-disconnect couplings 5 are used throughout the assembly. Onesuch fitting is manufactured by Colder Products and requires only onehand to operate. The fittings 5 are FDA approved and are readilyavailable.

The assembly of the tubing 19 to the fittings 5 may be accomplished bypushing the tubing 19 onto tapered bosses 22. No barbs on the bosses arenecessary due to the low pressure of the system. An alternative optionwould be to solvent bond or U.V. bond the tubing 19 to the taperedbosses 22.

Centrally located on the underside of the organ container cover or lid 9is a standpipe or adaptor 7. This adaptor is connected to the bottom ofcover 9 by means of a quick disconnect coupling 5. The adaptor isdesigned so that, for example, in case of a human heart the aorta may beattached to it.

While a cylindrical organ container is disclosed other cross-sectionssuch as oval or rectangular may be used.

The oxygenator 21 is in the form of a hollow chamber with a cover 14 andis attached to the organ container 8. The cover 14 is equipped with 3quick connect fittings 5 a, 5 b and 5 c and one check valve 13 throughwhich gases may be vented to the atmosphere. The quick connect fittings5 are color coded so that improper connections may be avoided. Quickconnect oxygen inlet fitting 5 a communicates with the interior of theoygenator 21 by means of 4-6 gas permeable Silastic.RTM. tubes 22through which oxygen is transferred to the perfusion fluid in theoxygenator 21. The flow of oxygen through the tubes is opposite to thedirection in which the perfusion fluid flows through the oxygenator 21.This increases the efficiency of oxygen transfer to the fluid. Thetubing is manufactured by Dow-Corning and is sold under catalog number508-006. The tubing 22 has an inside diameter of 0.058 inches or 1.47 mmand an outside diameter of 0.077 inches or 1.96 mm. The oxygenator tubesare 24 inches long. Quick connect fittings 5 b and 5 c communicate withthe interior of the oxygenator 21 and are used to supply used perfusionfluid for oxygenation through fitting 5 c and withdraw oxygenatedperfusion fluid through fitting 5 b. Excess oxygen is bled to theatmosphere through check valve 5 d so as to avoid foaming and bubbles inthe perfusion fluid.

While our device uses a particular type of Silastic.RTM. tubing for gasexchange it should be understood that other silicone tubing or othermaterials may be used. For example, polyethylene is permeable to oxygenand carbon dioxide but not to aqueous solutions, it is, however, rigid.Thin polyethylene sheets can be used to make a functioning oxygenator inan assembly like an automobile radiator.

The bubble chamber 11 is in the form of a hollow chamber with a lid 11a. The chamber 11 has an upper portion 11 b and a lower portion 11 c.The cross-sectional area of the upper portion 11 b of the chamber 11 islarger than the cross-sectional area of the lower portion 11 c. Thelower most portion of the upper and lower portions of the chamber 11 areprovided with quick connect fittings 5 which communicate with theinterior of the chamber 11. The cover 11 a of the chamber 11 is equippedwith a one-way stopcock 12 through which gases are vented to theatmosphere.

It will be readily apparent to those skilled in the art that other formsof bubble chambers may be used such as one having a differentcross-sectional area.

The pump assembly 24 comprises a box 23 which contains a sealed leadacid 12 volt battery 31, a DC brush motor 32 and an AC transformer 33 tosupply 12 volt DC current to the motor when AC current is available. Themotor shaft extends through the box 23 and drives the pump 24. The pump24 is a peristaltic pump manufactured by APT Instruments and has acapacity of 8-10 milliliters/min/100 grams of organ weight. A humanheart weighs approximately 450 grams. The pump 24 is mounted to theoutside of the box 23 and the pump on-off switch 25 is mounted on thepump thus providing ready access. A pump r.p.m. gauge 26 is mounted onthe outside of the box 23. Pump r.p.m. is an indication of flow rate ofperfusion fluid. A pressure cuff 27 or pressure transducer 28 may bemounted on the fluid supply line A or inside a T-connection in case apressure transducer is used. A pressure readout gauge 29 is mounted onthe box 23. Appropriate pressure, temperature and fluid flow alarms (notshown) may be mounted on the box 23 or in another convenient locationsuch as on the cooler 2.

Other forms of pumps may be advantageously used, for example, syringepumps or centrifugal pumps may be readily substituted for the rotaryroller pump disclosed.

The invention is useful for the transport of human organs such as theheart, kidneys, livers, lungs and the pancreas. The operation of thedevice will be described in connection with a human heart.

When a heart donor becomes available the surgeon removes the heart fromthe donor in the sterile environment of an operating room.

The tray 3 carrying the organ container 8 and the attached oxygenator 21and bubble chamber 11 together with the pump assembly 4 and oxygenbottle 17 are present to receive the heart which is first emptied ofblood with perfusion fluid. This is standard procedure. The aorta isthen connected to the concave portion 7 a of the adaptor 7. The heart isthen suspended in the organ container 8 partially filled with perfusionfluid. The entire container 8 and the oxygenator 21 are then filled withfluid. The oxygen container 17 is connected to the oxygenator 21 bymeans of tube E.

The bottom of the organ container 8 has a perfusion fluid outlet 30,which is connected to the oxygenator inlet 5 c by means of tube C sothat used perfusion fluid can be transported to the oxygenator 21.

The outlet 5 b of the oxygenator 21 is connected to the pump 24 by meansof tube D so that oxygenated fluid can be pumped from the oxygenator 21to the pump 24 and by means of tube A into the bubble chamber 11 whereair bubbles and foam are removed from the fluid. Most of the bubblesform early during the course of perfusion.

From the bubble chamber the fluid travels from the bottom of the bubblechamber 11 through opening 31 through tube B into the adapter 7 to whichthe aorta has previously been sutured. The connection of the tube B toadapter 7 is the last connection made which assures that there is no airentering the aorta with the perfusion fluid.

The tray 3 is now placed in the cooler 2 and coolant blocks 6 are placedin the cooler to maintain the temperature in the cooler at approximately4.degree. C. to 6.degree. C.

All connections of the tubes A-E are made with color-coded quickconnect-disconnect fittings 5. Only one hand is needed to operate thefittings 5.

A heart is paralyzed just before it is harvested so that the donor heartis not contracting while being perfused. The oxygen requirements of anon-contracting heart cooled at 4.degree. C. is 1/100 of the oxygenconsumed by an actively beating heart at body temperature (37.degree.C.). The two-liter oxygen cylinder supplies 0.125 liter/minute oxygenfor more than 34 hours, or over 160% of the amount needed to supplyoxygen for a 24-hour period.

In our invention the rate of perfusion is controlled by controlling ther.p.m. of the pump 24. This may be accomplished by means of a pulsewidth modulator (PWM), which is a commercially available device.

It will thus be seen that we have provided for a portable organtransport device that will maintain the viability of an organ for atleast 24 hours. The device is compact in construction and light inweight.

The entire assembly is housed in a commercial cooler holdingapproximately 50 quarts and the total weight is approximately 50 pounds.

The many benefits of our invention include the ability to deliver organsin better physiological condition, to shorten recovery times, to reduceoverall cost, to increase the available time to improve tissue matchingand sizing of the organ, to perform clinical chemistries and diagnostictesting for infectious diseases prior to transplantation, to enlargeselection of donor organs, to widen the range of available organs, toprovide surgical teams with more predictable scheduling and relievingtransplant centers of crisis management. Finally, the invention createsthe feasibility of a worldwide network of donors and recipients.

1. Apparatus comprising a perfusion fluid loop for maintaining an exvivo organ in viable condition for transplantation, said perfusion fluidloop comprising: an organ container for receiving an organ to betransported, a bubble remover for removing gas bubbles from perfusionfluid disposed in said perfusion fluid loop, and an oxygenator forsupplying oxygen to and removing carbon dioxide from perfusion fluiddisposed in said perfusion fluid loop.
 2. The apparatus of claim 1,which is a compact assembly for transportation of an organ.
 3. Theapparatus of claim 1, further comprising a pump for circulating aperfusion fluid in said perfusion fluid loop.
 4. The apparatus of claim3, in which said perfusion loop further comprises a flexible tube andsaid pump comprises a peristaltic impeller for driving fluid flow insaid flexible tube.
 5. The apparatus of claim 1, further comprising anouter container for carrying said perfusion fluid loop.
 6. The apparatusof claim 1, further comprising tubing for connecting said organcontainer, bubble remover, and oxygenator to define said perfusion loop.7. The apparatus of claim 6, further comprising quick connect-disconnectcouplings for connecting said tubing to said organ container, bubbleremover, and oxygenator.
 8. The apparatus of claim 7 in which said quickconnect-disconnect couplings are color-coded.
 9. The apparatus of claim1, further comprising a perfusion fluid disposed in said perfusion fluidloop.
 10. The apparatus of claim 1, in which said bubble remover is aseparate chamber from said oxygenator and said organ container.
 11. Theapparatus of claim 1, in which said oxygenator is a separate chamberfrom said organ container and said bubble remover.
 12. The apparatus ofclaim 1, in which said organ container is a separate chamber from saidoxygenator and said bubble remover.
 13. The apparatus of claim 1, inwhich said perfusion fluid loop comprises a headspace positioned forcollecting a gas from perfusion fluid and a venting valve communicatingwith said headspace, through which a gas may be vented to theatmosphere.
 14. The apparatus of claim 13, in which said venting valveis a check valve to permit flow of fluid out of said perfusion fluidloop.
 15. The apparatus of claim 1, in which said organ container has aninlet and an outlet for perfusion fluid.
 16. The apparatus of claim 1,further comprising an adapter having a first portion defining aperfusion fluid inlet and a second portion adapted for connection to avessel of an organ in said organ container, for directing perfusionfluid into the vessel.
 17. The apparatus of claim 16, wherein saidadapter fluid inlet comprises a quick connect-disconnect hoseconnection.
 18. The apparatus of claim 16, in which said organ containercomprises a cover having an inside portion and an outside portion. 19.The apparatus of claim 18, in which said adapter is connected to theinside portion of said cover.
 20. The apparatus of claim 16, in whichsaid organ container has an opening sized to pass an organ into saidorgan chamber, normally closed by a cover in use, said cover having aninside portion and an outside portion.